Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance

Lidia Wrobel, Sandra M. Hill, Alvin Djajadikerta, Marian Fernandez-Estevez, Cansu Karabiyik, Avraham Ashkenazi, Victoria J. Barratt, Eleanna Stamatakou, Anders Gunnarsson, Timothy Rasmusson, Eric W. Miele, Nigel Beaton, Roland Bruderer, Yuehan Feng, Lukas Reiter, M. Paola Castaldi, Rebecca Jarvis, Keith Tan, Roland W. Bürli and David C. Rubinsztein ()
Additional contact information
Lidia Wrobel: Cambridge Biomedical Campus
Sandra M. Hill: Cambridge Biomedical Campus
Alvin Djajadikerta: Cambridge Biomedical Campus
Marian Fernandez-Estevez: Cambridge Biomedical Campus
Cansu Karabiyik: Cambridge Biomedical Campus
Avraham Ashkenazi: Cambridge Biomedical Campus
Victoria J. Barratt: Cambridge Biomedical Campus
Eleanna Stamatakou: Cambridge Biomedical Campus
Anders Gunnarsson: Biophysics SE, Discovery Sciences, R&D, AstraZeneca
Timothy Rasmusson: Discovery Biology, Discovery Sciences, R&D, AstraZeneca
Eric W. Miele: Discovery Biology, Discovery Sciences, R&D, AstraZeneca
Nigel Beaton: Biognosys AG
Roland Bruderer: Biognosys AG
Yuehan Feng: Biognosys AG
Lukas Reiter: Biognosys AG
M. Paola Castaldi: Discovery Biology, Discovery Sciences, R&D, AstraZeneca
Rebecca Jarvis: Discovery UK, Neuroscience, BioPharmaceuticals R&D, AstraZeneca
Keith Tan: Discovery UK, Neuroscience, BioPharmaceuticals R&D, AstraZeneca
Roland W. Bürli: Discovery UK, Neuroscience, BioPharmaceuticals R&D, AstraZeneca
David C. Rubinsztein: Cambridge Biomedical Campus

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for a number of neurodegenerative diseases, especially Huntington’s disease and various spinocerebellar ataxias. Ideally, such approaches should preferentially clear the mutant/misfolded species, while having minimal impact on the stability of wild-type/normally-folded proteins. Furthermore, activation of both ubiquitin-proteasome and autophagy-lysosome routes may be advantageous, as this would allow effective clearance of both monomeric and oligomeric species, the latter which are inaccessible to the proteasome. Here we find that compounds that activate the D1 ATPase activity of VCP/p97 fulfill these requirements. Such effects are seen with small molecule VCP activators like SMER28, which activate autophagosome biogenesis by enhancing interactions of PI3K complex components to increase PI(3)P production, and also accelerate VCP-dependent proteasomal clearance of such substrates. Thus, this mode of VCP activation may be a very attractive target for many neurodegenerative diseases.

Date: 2022
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DOI: 10.1038/s41467-022-31905-0

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